AU716665B2 - Medicament intended to the treatment of obsessive compulsive troubles, sleep apnoea, sexual dysfunctions, emesa and transport sickness - Google Patents

Description

t I The present invention relates to the use of 1-{4- [4-aryl (or heteroaryl)-l-piperazinyl]butyl}-iH-azole derivatives, as well as to their physiologically acceptable salts, for the manufacture of medicaments for use in the treatment of compulsive obsessive disorders, sleep apnoea syndrome, sexual dysfunctions, emesis and travel sickness.

The compounds to which the present invention relates have been described in European Patents EP-0,382,637 and EP-0,497,659, as well as in European Patent EP-0,502,786 which relates to a process for the preparation of aryl (or heteroaryl)-piperazinyl-butylazole derivatives. In Patents EP-0,382,637 and EP-0,497,659, we have claimed the use of these compounds for the treatment of certain diseases of the central nervous system. We have now discovered that aryl (or heteroaryl)-piperazinyl-butyl-azole derivatives show antiobsessive activity, activity towards preventing sleep apnoea syndrome, activity which facilitates sexual behaviour, and antiemetic and antinausea activity and they are consequently useful in therapy for the prevention and treatment of compulsive obsessive disorders, sleep apnoea syndrome, sexual dysfunctions and nausea and vomiting induced, in particular, by cytotoxic radiotherapy and/or chemotherapy or movement. In particular, the compounds are for use in the preventive or curative treatment in man and animals of depression compulsive obsessive disorders, sleep apnoea syndrome, sexual dysfunctions, emesis and travel sickness.

The compounds recommended within the context of the present invention correspond to the general formula

I

Z

4

C-R

3 Ar-N N--(CH2)4--N (Z2

(I)

in which -2- Ar represents a nitrogenous or non-nitrogenous aromatic radical chosen from variously substituted aryls, variously substituted 2-pyrimidine, and 3-(1,2benzisothiazole), Z1 represents a nitrogen atom or a substituted or unsubstituted carbon atom which may be represented by: C-R,, Z2 represents a nitrogen atom or a substituted or unsubstituted carbon atom which may be represented by: C-R 2 Z4 represents a nitrogen atom or a substituted or unsubstituted carbon atom which may be represented by: C-R 4 and R 1

R

2

R

3 and R 4 which are identical or different and may also form part of another aromatic or non-aromatic ring, represent a hydrogen atom, a halogen, a C,-C6 alkyl radical, a nitro radical, a hydroxyl radical, a alkoxy radical, a cyano radical, a hydroxycarbonyl radical, a Cl-C, alkoxycarbonyl radical, an aryl or substituted aryl radical, a sulphonic radical, a sulphonamido radical, an S 15 aminocarbonyl radical, which may or may not be substituted on the amino group, an amino or substituted amino radical, and their therapeutically acceptable salts.

When Ar represents a variously substituted aryl, it is preferably a radical S: of formula R R7 in which R 7

R

8 and R, which are identical or different, represent a hydrogen atom, a halogen, an alkyl radical, a perhaloalkyl radical, a hydroxyl radical, an alkoxy radical or a cyano radical.

According to the invention, the term alkyl is understood to refer to lower alkyls, preferably linear or branched, optionally unsaturated alkyls, in particular the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl and hexyl radicals and their various isomers. This definition also applies for the alkyl residues of the alkoxy radicals.

H:\apps\winwordUENNYjennyM'Neiispecnki'13764-97.DOC 3 According to the present invention, the term halogen is preferably understood to refer to fluorine, chlorine, bromine or iodine.

According to the invention, the term aryl is understood to refer in particular to an aromatic or heteroaromatic radical chosen, in particular, from the phenyl, naphthyl, anthryl, phenanthryl, pyridyl, pyrimidyl, etc. radicals, preferably phenyl, optionally substituted, in particular with one or more radicals selected from halogens, lower alkyl, nitro, hydroxyl, alkoxy, cyano, hydroxycarbonyl, alkoxycarbonyl, aryl or substituted aryl, sulphonic and sulphonamido radicals, aminocarbonyl radicals, which are substituted or unsubstituted on the amino group, and amino or substituted amino radicals.

The substituents of the amino group are, in particular, alkyl or aryl radicals.

The term therapeutically acceptable salts is understood to refer to the usual salts of addition of organic or inorganic acids, such as the hydrochlorides, dihydrochlorides, mesylates or tosylates.

The compounds identified in Examples 1 to 84 below are obtained by the procedures described in Patents EP-0,382,637, EP-0,497,659 and EP-0,502,786, and the data for their identification are detailed in Table I.

EXAMPLES

1. l-{4-[4-(2-pyrimidinyl)-l-piperazinyl]butyl}pyrrole, 2. 1-{4-[4-(2-pyrimidinyl)-l-piperazinyl]butyl}carbazole, 3. l-{4-[4-(2-pyrimidinyl)-l-piperazinyl]butyl}indole, 4. 2,3-diphenyl-l-{4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl}indole, 4-carboxamido-l-{4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl}-1H-pyrazole, 6. 4-carboxy-l-{4-[4- :2-pyrimidinyl)-1-piperazinyl]butyl}-IH-pyrazole, 7. 3-methyl-5-trifluoromethyl-l-{4-[4-(2-pyrimidinyl)- 1-piperazinyl]butyl}-lH-pyrazole, 8. 4,5-diphenyl-l-{4- [4-(2-pyrimidinyl) -1-piperazinyl]- -4 butyl) -1H-imidazole, 9. 2,,-rpey--4 4 2prmdnl 1pprz inyl] butyl}-1H-imidazole, 4,5-diphenyl-2-methyl11-{4- (2-pyrimidinyl) -1piperazinyl] butyl}-1H-imidazole, 11. 4,5-dichloro-2-methyl-1-{4- (2-pyrimidinyl) -1piperazinyl] butyll -1H-imidazole, 12. 2-ty--4 4 2prmdnl 1pprznl butyl) -lH-imidazole, 13. 2-phenyl-1-{4- (2-pyrimidinyl) -1-piperazinyl] butyl) -1H-imidazole, 14. 4 -methoxycarbonyl -1 (2 -pyrimidinyl) -1I-piperazinyl] butyl)-1H-imidazole, 4-phenyl-1-{4- (2-pyrimidinyl) -1-piperazinyl] butyl)-1H-imidazole, 16. (2-pyrimidinyly) 1-piperazinybutyl11Hbenzimidazole, 17. (2-pyrimidinyl) -1-piperazinyllbutyl}-3Himidazo pyridine, 18. (2-pyrimidinyl) -1-piperazinyllbutyl)-1Himidazo pyridine, 19. 1 [4 (2 -pyrimidinyl) -i1-piperazinyll butyl}-1Hbenzotriazole, 2-hool{-[-(-yimdnl 1pprznl butyl) -lH-benzimidazole, 21. (2-pyrimidinyl) -1-piperazinyllbutyl}-1H- 1, 2,4 -triazole, 22. (2-pyrimidinyl) -1-piperazinyllbutyl}-2Hbenzotriazole, 23. 2-ehll{-[-(-yimdnl 1pprznl butyl} -1H-benzimidazole, 24. 5,6-dimethyl-1-{4- (2-pyrimidinyl) -1-piperazinyl] butyl) -1H-benzimidazole, (2-pyrimidinyl) -1-piperazinyll]buty1l 1H- -pyrazole, 26. 3,5-dimethyl-1-{4- (2-pyrimidinyl) -1-piperazinyl] butyl)}- 1H-pyrazole, 27. 3,5-dimethyl-4-fitro--{4[4(2-pyrimidinyl)-1 piperazinyl) butyl} -1H-pyrazole, 28. 4-methyl-1-{4- (2-pyrimidinyl) -1-piperazill butyl} -1H-pyrazole, 29. (2-pyrimidiny1) -1-piperaziflbutyl}-1Himidazole, 4-bromo-3, 5-dimethyl-1-{4-[4- (2-pyrimidinyl) -1piperazinyl] butyl) -1H-pyrazole, butyl) -1H-pyrazole, 32. 4-hool{-[-(-yimdnl 1pprznl butyl) -1H-pyrazole dihydrochioride, 33. 4-ethoxycarbonyl-1-{4- (2-pyrimidinyl) -1-piperazinyl) butyl)-lH-pyrazole, 34. 3-methyl-5-pheflyl-1-{4- (2-pyrimidinyl) -1-piperazinyl] butyl}-1H-pyrazole, 4-rm--4 4 2prmdnl 1pprznl butyl} -1H-pyrazole, 36. 4-yn--4[-2prmidnl--ieaiyl butyl) -1H-pyrazole, 37. 4-fluoro-1-{4- (2-pyrimidil) -1-piperazifll butyl) -1H-pyrazole, 38. 4-mn--4 4 2prmdnl 1pprznl butyl} -1H-pyrazole, 39. 4-methylsulphonamido-1-{4- (2-pyrimidinyl) -1piperazinyl] butyll-lH-pyrazole, 4-benzamido-1-{4- (2-pyrimidinyl) -1-piperazinyl] butyl} -1H-pyrazole, 41. 4-acetandido-1-{4- (2-pyrimidinyl) -1-piperazinyl] butyl}-1H-pyrazole, 42. 4-(2-butyl)amino-1-{4-[4-(2-pYrimfidifylYV-pi'perazinyl] butyl} -1H-pyrazole, 43. 3-chloro-4-fluoro-l-{4- (2-pyrimidil) -1piperazinyl] butyl}-1H-pyrazole, 44.- 4- (4-methoxyphenyl) (2-py-rimidinyl) -1-piperazinyl] butyl)-1H-pyrazole, 4- (4-chiorophenyl) (2-pyrimidinyl) -1-piperazinyl] butyl}-1H-pyrazole, -6 azinyl) butyl}-1H-pyrazole, 47. 4-phenyl-1-{4- (2-pyrimidinyl) -1-piperazinyl] butyl} -1H-pyrazole, 48. 3,5-diphenyl-1-{4- (2-pyrimidinyl)-1-piperazinyl] butyl)l H-pyrazole, 49. 4-phenylsulphanioyl-1-{4- (2-pyrimidinyl) -1-piperazinyl] butyl) H-pyrazole, 4- (4-methylbenzene)sulphamoyl-1-{4- (2-pyrimidinyl) -1-piperazinyl] butyl}-1H-pyrazole, 51. 4-butylsulphamoyl-1-{4- (2-pyrimidinyl) -1-piperazinyl] butyl}-1H-pyrazole, 52. 4-propylsulphanloyl-1-{4- (2-pyrimidinyl) -1-piperazinyl] butyl}-1H-pyrazole, 53. 4 -ethylsulphamoyl {4 (4 (2 -pyrimidinyl) -1I-piperazinyl] butyl}-1H-pyrazole, 54. 3,5-dimethyl-4-(N,N-dimethylBulphoflamido)-l- {4-[4-(2-pyrimidiny1)-1-piperaziflbutyl).1Hpyrazole, 55. 4-N-methylsulphamoyl-1-{4- (2-pyrimidilyl) -lpiperazinyl] butyl}-1H-pyrazole, 56. 4-Bulphonic-1-{4- (2-pyrimidinyl) -1-piperazinyl] butyl) -1H-pyrazole, 57. 1-{4-[4-(2-pyrimidiny1)-1-piperazifl1butyl) 1-imidazole, 58. 2-methyl-1-{4- 4- (2-pyrimidilyl) -1-piperazinyl] butyl} -1H-imidazole, 59. 4,5-dichloro-1-{4- (2-pyrimnidinyl) -1-piperazinyl] butyl) -1H- imidazole, 60. 4-chloro-1-{4- (4-methoxyphenyl) -1-piperazinyl] butyl} -1H-pyrazole, 61. 4,5-dichloro-2-methyl-1-{4- (4-methoxyphenyl) 1-piperazinyl] butyl) -1H-imidazole, 62. 4 -chl oro 1-{4 4- (2 -methoxyphenyl) 1-piperaz inyl]I -butyl}-1H-pyrazole, 63. 4,5-dichloro-2-methll-{4- (2-methoxyphenyl) 1-piperazinyl] butyl}-1H-imidazole, 64. 4-chloro-1-{4- (3-methoxyphenyl) -1-piperazinyl] N, butyl}-1H-pyrazole, -7 (4-methoxyphenyl) -1-piperazinyllbutyl~pyrrole, 66. (2-mnethoxyphenyl) -i-piperazinyllbultyllpyrrole, 67. (phenyl) -1-piperazinyllbutyl}pyrrole, 68. 4-chloro-1-{4- (phenyl) -1-piperaziflyllbutyl}-1Hpyrazole, 69. 4, 5-dichloro-2-methyll{4- 4- (phenyl) -1-PiPerazinyl] butyl} -1H-imidazole, 70. 4-hool{-4(-horpey)lpprznlbutyl) -lH-pyrazole, 71. 4, 5-dichloro-2-methyl-l-{4- (2-chlorophelyl) 1-piperazinyl] butyl} -lH-imidazole, 72. 4-chloro-l-{4- [4-(3-chlorophenyl)-l-piperazilyl] butyl)-1H-pyrazole, 73. 4,5-dichloro-2-methyl-1-{4-[4-(2-cyanophenyl)- 1-piperazinyl] butyl} -lH-imidazole, 74. 1-piperazinyl] butyl)-1H-imidazole, 75. 4-hoo11-[-(-ynohnl 1pprznl butyl) -lI{-pyrazole, 76. 4,5-dichloro-2-methyl-1-{4- (3-trifluoromethylphenyl) -1-piperazinyl]butyl)-1H-imidazole, 77. 4-chloro-l-{4- (3-trifluoromethylphelyl) -1-piperazinyl] butyl}-lH-pyrazole, 78. 4-chloro-l-{4- (4-(2-fluorophenyl)-1-piperazilyl] butyl} H-pyrazole, 79. 4-hool{-4(,-ezstizl3y)lppr azinyl] butyl}-lH-pyrazole, 80. 4,5-dichloro-2-methyl-1-{4- (1,2-benzisothiazol- 3-yl) -1-piperazinyl]butyl}-lH-imidazole, 81. [4-(1,2-benzisothiazol-3-yl)-1-piperazillbutyl}-1H-1, 2, 4-triazole, 82. (4-(1,2-benzisothiazol-3-y)--piperazillbu y1}-1H-benzimidazole, 83. 4-bromo-1-{4- (5-bromopyrimidin-2-y1) -1-piperazinyl] butyll-lH-pyrazole, 84. 4-hoo{-[-(-rmpyiii--l 1ppr azinyl] butyl)-lH-pyrazole.

TABLE I

N

N

N (CH- 2 4 -N 7:-

~Z

2 Example Z 1

Z

2 Z 4

R

3 M. P. IR crn 1 1 s~Nt 1 H-NMR (100 MHz), 8, J=Hz 2941, 1585, 1.55 (in, 2H); 1.77 (n 1547, 1500, 2H); 2.25-2.55 6H);1 1CH CH cif i oil 1360, 1260, CDC1 3 3.70-4,05 6H); 6,13 983, 724 J=2, 0Hz, 2H) 6. 47 (film) I(t, J=4, 7Hz, 1H); 6,65 J=2, 0Hz, 2H1); 8. 29 2941, 1586, 1,.6 (mn, 2 H) 1. 86 (in, 1547, 1511, 2H); 2,27-2,45 68); 1494 1402, 3,78 J=5, 2Hz, 4H);.

2 C-CH=CH-CH=CI1-C C-CH=.CH-CI1=.CH- Oil 1359, 1307, CDC1 3 4, 30 J=7, 1Hz, 28); 1260, 983, 6,43 J=4, 7Hz, 1H); 750, 723 7,12-7,46 6H) 8, 07 (film) J=6, 5Hz, 211); 8,26 711z, 2H) -2940, 1585, 1, 54 28H) 1, 88 (rn, 1547, 1510, 2H) 2,37 61f); 3, 79 3 C-CH=C~i-CH=CH-C CH If oil 1446, 1359, CDC1 3 J=5Hz, 4H), 4113 (t, 1259, 983, J=6, 8Hz, 2H); 6.45 (a.c.

741 (film) 2H) 6,9-7.1 8. 27 J=4, 7Hz, 2H) TABLE I (continued) N R N N-(CH 2

J

4

N

2 N 71 -Z Example 1 2

Z

4 R3 m.p. IR cm 1 solveNMR H-NMR (100 MHz) 8, J=Hz 2942, 1586, 1,38 2H); 1,68 2H); 1547, 1502, 2,10-2,40 6H); 3.76 1447, 1359, J=5Hz, 4H); 4,11 (t, S C-CH=CH-CWH=CH-C CPh Ph oil 1261, 984 CDC13 J=7Hz, 2H); 6,41 J=4, 789, 757, 7Hz,.1H); 7.10-7.50 (a.c.

702 (film) 13H); 7.79 1H); 8.25 J=4, 7Hz, 2H) 3337, 3156, 1,38 2H); 1,81 2H); 1663, 1601, 2.3-2,5 6H); 3.69 (m, o 1586, 1446, 4H); 4,14 J=7Hz, 2H); N CH CH 1 124-C 1360, 980 DMSO-d 6 6,6 J=4, 7Hz, 1H); -crl (KBr) broad 1H); 7,7 (broad 11); 7.89 (s, 1H); 8,24 l1I); 8,35(d, J=4, 6Hz, 2H) 3100, 2943, 1.40 2H); 1,81 (mn, 2H); 1602, 1587, 2,23-2,49 6H); 0 1546, 1487, (broad 1H); 3.64 (m, 6 N CH CH 104- 1440, 1360, DMSO-d 6 4H); ,4.13 (t J=71z, 211) 105 0 C 1260, 797 6,6 J=4, 7Hz, 1H); 7,7 (film) 1H); 8,1 1H); 8.33 J=4, 7Hz, 2H) TABLE I (continued) N N (C H 2.

4 -N Z rR N Z \Z 2 Example Z 1 1 Z 2 Z4 R 3 M. P. I IR cm- 1 sovn j 1 H-NMR (100 MHz), 5, J=Hz 2937, 2856, 1.57 2H); 1,89 (in, 1586, 1544, 2H); 2.32 3H); 2.30- 1496, 1393, 2,55 6H); 3,82 (t, 7 NCMe CCF3 H 71- 1228, 1177, CDC1 3 J=5Hz, 4H); 4,10 (t, 7 5 aC 1125, 981 J=7Hz, 2H); 6,25 1H); MKr) 6.47 J=4, 7Hz, 1H); 8.29 J=4, 7Hz, 2H) 2942, 1585, 1,55 (in, 4H); 2,16-2.42 1547, 1505, 6H) 3.71-3,89 1145, 1360, c 6H) 6. 47 J--l 8 CHi CPh Ph Oil 1307, 1260, CDC1 3 7Hz, 111); 7 .12-7,.60 (a c.

983, 774, 1H ,7(,J4 1z 754, 7002H ilm) 2942, 1585,1,5(,4)19-23 1546, 1501, 1) .940 9 CPh N CPh Ph oil 14 45 1360, CDC1 3 (a 6H) 6. 47 J=4, 1260, 983, 7Hz, 1H); 7,13-7,67 (a.c.

698 (film) 15H); 8.26 J=4, 7Hz, 2H) TABLE. I (continued) N N N-(CH 2 4 N 4 rR NZI z 2 Example Z 1 Z2Z4R 3 M. p.f IR cm- 1 NMR ,JH Isolventl'-M~O ,JH 2942, 1585, 1. 43 (in, 4H1); 2.18-2.47 1547, 1500, 9H1); 3.72-3,76 CMe N CPh Ph Oil 1446, 1393, CDC1L 3 6H); 6.47 J=4, 1260, 9q3, 7Hz, 1H); 7,09-7.39 (a.c.

760, 698 1011); 8,26 J=4, 7Hz, __(film) 2H1) 2942, 1586, 1.45-1,84 4H1); 1547, 1500, 2,26-2.57 911) 11CMe N CCI C1 oil 1447, 1359, CDC1 3 3,74-4.05 6H) 6, 48 1259, 1245, J=4, 7Hz, 1H); 8. 983 (film) J=4, 7Hz, 2H1) 2938, 1585, 1.34 J=7, 1, 3H1); 1547, 1495, 1,66 (in, 4H); 2.31-2,72 12 CEt NCH H oil 1446, 1360, CDC1 3 8H1); 3,77-3,92 1260, 983, c. 611) 6,47 J=i, 638 (filmn) 7Hz, 111); 6, 87 (d, J=1OHz, 8.26 (d, J=4, 7Hz, 211) TABLE I (continued) Z, z 2 Example Z 1

Z

2 Z. IR cm 'HI-NMR(100 MHz), 6, J=Hz -FZ- Isolvent H-NMR MIz) Jsolvent= 2941, 1585, 1.45 2H); 1.73 (m, 1547, 1500, 2H); 2,19-2.42 6H); 1446, 1360, 3,77 J=5, 1Hz, 4H); 13 CPh Ii CH Oil 1260, 983, CDC13 4,01 J=7, 3Hz, 2H); 774, 700 6,47 J=4, 7Hz, 1H); (film) 6.94-7,61 7H); 8.27 J=4, 7Hz, 2H) 2800, 1713, 1,45 2H); 1,72 (m, 1585, 1544, 2H); 2,29-2.39.(a.c. 6H); 0 1483, 1360, 3.65-3.74 7H); 4.01 14 CH N CH 92- 1223, 1117, CDC1 3 J=6, 8Hz, 2H); 6.47 ce 94C 985 (KBr) J=4, 7Hz, 1H); 7.67 1H); 7.81 1H); 8.24 J=4, 7Hz, 211H) 2944, 1585, 1,45 2H); 1.73 (m, 1548, 1500, 2H); 2,21-2,45 6H); 1447, 1360, 3.,60-3,75 411); 4.03 CH N CH Ph 105- 1260, 983 DMSO-d 6 J=6, 8Hz, 2H); 6.47 107 0 C (KBr) J=4, 7Hz, 1H); 7.21- 7.79 7H); 8,25 (d, J=4, 7Hz, 2H) TABLE I (continued) N

R

N N-(C 2 4 -N f ~z 2 N Z

IR

3 Mcm nt 1 'J-NMR (100 MHz), 6, J=Hz 2944, 1581, 1.40 2H); 1.82 21); 1542, 1488, 2,26-2,42 61); 3,62-3j71 1466, 1355, 4H); 4.24 J=6, 9Hz, 16 CH N C-CH=C[H-CH=CH- 85- 1259, 741 DASO-d 6 2H); 6.56 J=4, 7Hz, 1H); 88 0 C (KBr) 7.16-7,26 2H); 7,55-7,70 2H);.8.22-8.34 3H) 2935, 1578, 1,45 2H); 1.90 21); 1545, 1482, 2.23-2,50 61); 3,6 (t, 1443, 1409, J=4, 8Hz, 4H); 4,3 J=7, 17 CII IA C-M=CI-CH=CCH- 104VC 1357, 1256, DMS0-d 6 0Hz, 2H); 6.5 J=4, 7Hz, 982, 751 11H); 7,25 J=4, 7Hz, 1H); (KBr) 8,05 J=7, 9Hz, 1H); 8.30- 8,48 4H) 2944, 2828, 1.42 21); 1.,84 211); 1609, 1582, 2,28-2,49 6H); 3,60-3,69 1543, 1487, 4H); 4.03 J=7, 0Hz, 18 CHi N C-CH=CH-CH=N- 134 C 1460, 1355, DMSO-d 6 2H); 6.5 J=4, 7Hz, 11); 1260, 982, 7.28 (dd, J4, 7Hz, 1H); 8,07 800 (KBr) J=7, 9Hz, 1H); 8,29-8.50 4H) TABLE I (continued) N N N (CHZ) 4 -N 4::rR Z2 N z 2 ExampI rnp R cm- I s~~i tM 'H-NMR (100 MHz), 6, J=Hz 2940, 2818, 1.43 (in, 211); 1.97 (mn, 1590, 1544, 211); 2.24-2,53 6H1); 1498, 13i60, 3. 66 1Hz, 4H); 19 N N C-CH=CH-CH=CH- 89- 1259, 984, DMSO-d 6 4 .75 J=6, 8Hz, 2H1); 50 7 49 MKr) 6. 60 J=4, 7Hz, 1H1); C 7,52 (mn, 2,H) 8.01 (m, 2H1); 8,31 111); 8,36 1H1) 2940, 1583, 1.50 (mn, 2H1); 1,81 (in, 1542, 1491, 211); 2,20-2.42 61f); 1466, 1443, 3.67 Cm, 4H1); 4, 28 (t, CC1 N C-CH=CHCH=CH 153- 1383, 1264, DMSO-d 6 J=7Hz, 211); 6,58 J=4, 0 C 1128, 981, 7Hz, 111); 7.30 (in, 2H1); 742 (KBr) 7.60 (mn, 2H1); 8,31 (d, J=4, 7Hz, 2H1) TABLEII (continued) N N N- (CH 2 4 -N /4 R \i -Z 2 Example Z 4R 2 M. P. IR cm- 1 NMR 'H4JN4R 100 MHz), 8, J=Hz 1 I II 1 1 solventi 2942, 1582, 1,55 (in, 2,H) 1. 96 (in, 1546, 1458, 2H) 2.32-2.51 6H); 1448, 13160, 3.81 J=5, 1Hz, 4H) 21 CH N HN 69- 1261, 1138, CDC1 3 4.21 J=7, 0Hz, 211) 71*C 1011, 983, 6, 47 J=4, 7Hz, 1H);- 680 (KBr) 7,95 8,09 (s, IH); 8,29 J=4, 7Hz, 2946, 2863, 1,34-1,56 (mn, 2H1); 1.97- 2823, 1585, 2.13 2H); 2,18-2,48 1547, 1483, 6H); 3,65 1358, 1256, 3Hz, 4H); 4,75 J=6, 22 N N -CH=CIIhCICH-C 97,4- 982, 799, DHSO-d 6 8Hz, 2H); 6, 56 J=4, 98, 2*C 761 (KBr) 7Hz, 1H); 7, 40 (dd, J=6, 31=3, 1Hz, 2H); 7,90 (dd. J=6, 6Hz, JI=3, 3Hz, 2H) 8. 28 1H); 8. 33 1H) TABLE I (continued) M. P. IR cm'1 1NR 'H-NMR (100 MHz), 6, J=Hz Z2 solvent 2938, 2820, 1,56-1.93 4H); 1583, 1542, 2,30-2,47 6H); 2,58 1494, 1 05, 3H); 3,79 N 101- 1357, 1~ 58, CDC1 3 2Hz, 4H) 4.10 J=7, 102-C 983, 79B, 3Hz, 2H) 6, 43 J= 4, 744 (KBr) 7 Hz, 1H) 7. 22 (mn, 3H); 7. 67 (mn, 1H); 8,26 (d, 3=4, 7Hz, 2H1) 2916, 1584, 1.50 (in, 2H) 1,85 (in, 1542, 1491, 2H) 2.25-2,43 (a.c.

1466, 1362, 12H) 3,.76 J=5, 0Hz, N 105- 1262, 9B3, CDC1 3 4H1) 4. 07 3=7, 0Hz, 106*C 800, 742 2H) 6, 40 J=4, 7H-z, (KBr) 1H) 7. 11 Ili) 51 1H1); 7,71 1H); 8,23 J=4, 7Hz, 2K) TABLE I (continued) N-N

N-(CH

2 4

-N

N/ Z z 2 Example Z 1 Z R3 Z4 m.p. IR cm 1 NMR 'H-NMRO(100 MHz), 6, J=Hz solvent 2942, 2015, 1.50 (in, 2H); 1.90 2H); 2.,40 (m, 1586, 1547, 6H); 3.80 4H); 4.12 2H, J=6, 983 (film) 6..20 1H, J=l, 6.40 (t, N CI H CH Oil CDC1 3 1H1, J=4, 7.42 (dd, 2H, J=4, 7; 8.25 2H, J=4, 7) 1590, 1550, 1.58 2H); 1. 85 2H); 2.20 (s, 1350, 1260, 3H); 2,25 3H); 2.44 6H); 980 (film) 3.81 4H); 3.97 2H, J=7, 2); 26 N CHe I CMe Oil CDC1 3 5.7B 1H); 6.43 1H, J=4, 7); 2H1, J=4, 7) 1590, 1550, 1. 60 2H); 1.90 2H); 2.49 (m, 1350, 1260, 9H); 2.63 3H); 3,82 (min, 4H) 27 N CMe NO 2 CMe Oil 980 (film) CDC13 4,09 2H, 6.48 1H ,J=4, 8.29 2H, J=4, 7) TABLE I (continued) N

I-

N-(CH

2 4

-N

SZIZ

2 Example Z 1

Z

2 R3 Z 4 m.p. IR cm- 1 NMR H-NMR(100 MHz), 8, J=Hz solvent- S1590, 1550, 1.52 2H); 1.95 (in, 2H); 1500, 1360, 2.05 3H); 2.37 6H); 1260, 980 3,81 4H); 4,05 2H, 28 N CH Me CH Oil (film) CDC1 3 J=6, 6,41 IH, J=4, 7); 7,13 1H) 7.27 1H) 8.25 2H, J=4, 7) 2930, 1590, 1.51 2H) 1,98 2H) 1550, 1500, 2.36 6H) 3,77 (min, 4H); 29 N C1 -CH=CH-CH=CH-C- oil 1360, 1310, CDC1 3 4,39 2H, J=6, 6.40 (t, 1260, 980 IH, J=4, 7.0-7,7 (min, 4H); (film) 7,95 1H); 8,25 211H, 7) 2930, 1590, 1.55 2H) 1, 81 (min, 2H); 1550, 1500, 2.18 3H); 2,20 3H); N CMe Br CMe oil 1360, 1310, CDC1 3 2,38 (min, 4H); 3.80 (min, 4H); 1260, 980 3.99 2H, J=6, 6,42 (t, (film) IH, J=4, 8.25 2H, J=4, _7) TABLE I (continued)

N

N

/'Y

N- (CH 2 4

N

,z 2 Example Z 1

Z

2

R

3

Z

4 m.p. IR cm- 1 NMR IH-NMR (100 MHz), 5, J=Hz solvent 1584, 1524, 1,5 2H); 1,93 (m, 1480, 1444, 2H); 2,38 6H); 3.76 31 N CH NO 2 CH 94-96'C 1406, 1359, CDC1 3 4H); 4.15 2H, 1305, 8191 J=6, 7);6.42 1H, J=4, (KBr) 8.01 IH); 8.,12 1IH); 8.,24 2H, 7) 3429, 2688, 1.69 2H); 1,81 (m, 1636, 1620, 2H); 2, 98 2H); 3.08 32 N CH Cl CH 2 HCI 1346, 1218, DMSO-d 6 2H) 3.39-3,53 (m, 195-8°C 971 4H); 4.12 2h); 4,67 2H); 6. 77 1H); 7,53 1H); 8,04 (d, 8, 45 2H) 1715, 1586, 1.34 3H, J=7. 1); 1222, 983 1.54 2H); 1.90 (m, 33 N CI1 EtOOC- CH Oil (film) CDCI 3 2,46 6H); 3.,81 4 H) 4, 25 4H); 6, 47 1H, J=4, 7) 7. 90 2H); 8, 29 (d, 2H, J=4, 7) TABLE I (continued)

CN

N

N-(CH

2 4 -N

Z

.Z

2 Example Z Z 2 R3 Z 4 m.p. IR cm- 1

N

I

MR H-NMR(100 MHz), 5, J=Hz solvent 1586, 1547, 1.54 2H); 1.85 2H); 2,28 1360, 983 3H); 2,45 6H); 3,81 (m, (film) 4H); 4.07 2H, 6,28 (s, 34 N CMe H CPh Oil CDCl 3 1IH); 6.43 IH, J=4, 7,33 (in, 4H) 7.75 2H) 8, 26 (d, J=4, 7) 1586, 1547, 1.52 2H); 1,89 2H); 2,44 1360, 984 6H) 3.62 4H) 4, 11 (t, N CH Br CH oil (film) CDCI 3 2H, J=6, 6,46 1H, J=4, 7.42 1H); 7,45 IH); 8.29 2H, J=4, 6) 3076, 2231, 1,54 2H); 1,96 2H); 2 1587, 1551, 6H); 3,81 4H); 4,20 (t, 36 N CH C=-N CH 94-95°C 1258, 982 CDCI 3 2H, J=6, 6, 48 1H, J=1, (K r) 7.80 1H); 7,63 1H); .8.29 2H, J=4, 7) TABLE I (continued) N (C4J R3 (qH2)4 I Example Z 1 Z 2 RZ4 M. P. IR cm-1 'HNR(0 Mz,5,3 solvent -M(0Mz)

,JH

2944, 1584, 1.45 (mn, 1,96 (m, 1546, 1507, 2H); 2.36 6H1); 3.7 37 N C 1. F CH Oil 1359, 126Q, CDC1 3 (mn, 4.0 2H, J=6, 983 (film) 6. 47 1H1, J=4, 7); 7.27 (in, 2H, J=4, 8); 8.29 2H, J=4, 8) 1586, 1548, 1.50 (in, 2H); 1,85 (m, 1360, 984 211); 2,43 (mn, 6H1); 3.4 (film) Iarqie 2H); 3,8 (mn, 38 CH CHI H 2 N- N oil CDC13 611); 4 .0 Ct, 2H, J=6, 4); 6,.46 1H1, J=4, 7); 6.98 1H); 7,10 (s, 1 8,27 2H,_J=4,_7 1582, 1482, 1.58 2H); 1.93 (mn, 1360, 1150, 2H); 2. 45 6H) 2.94 983 MKr) 3H1); 3,8 4H); 39 CH CH Il[e-S0 2 -NH- N 13 2 C CDC1 3 4, 11 2H, 3= 6, 9) 6. 45 1K, 3=4, 7.4 11) 7,.5 I1H); 8, 28 2H, J=4, 7)

K,

H

TABLE I (continued) N 7.

4 N\ N (CHZJ 4 N ZI 2 Examplel Z 1 Z 2 J Z4 M. P. IR cin- 1 jNMR j H-NMR(100 MHz), 8, J=H-z 1646, 1586, 1. 55 (in, 1,79(s 1542, 1369 3H) 1. 88 (in, 2H) 2.42 I(in, 6H) 3. 80 (in, 41]); CH CH Ph-CO-NH- N 13 4- 13 6 C CDC1 3 4, 13 2H], J=6, 8) 6. 51 1H], J=4, 7) 7, 49 (mn, 7, 83 (m, 8,0 1H); 8,11 8. 28 21], 7) 1650, 1586, 1.50 (in, 1.88 (n 1454, 1364, 2,11 2,.43 1261, 983 (mn, 6H) 3, 79 (mn, 4H]) 41 CH CH- Me-CO-NH- N 8 0- 8 2C MKr) CDC1 3 4.8 2H, J=6, 8) 6. 47 1H], J=:4 7) 7. 36 (s,I 7. 93 0, 28 2H], J=4 9.25(s 1H) TABLE I (continued) N N- (CH' -N z 2 Example Z 1

Z

2

R

3 Z4 M.p. IR cm I NMR 'H-NMR (100 MHz), 5, J=Hz _solvent 2960, 1585, 1.00 3H, J=7, 1.19 Me 1547, 1359, 3 H, J=6, 3) 1, 6 (m, \CH-NIf- 1260, 983 4H); 1.90 2H); 2.50 (m, 42 CH CHI N Oil (film) CDC1 3 6H); 3,0 311); 3.9 (m, Et I 4H) 4. 1 2H, J=6, 8); 6, 52 IH, J=4, 6, 99 1H) 7.17 IH); 3.37 2H, J=4, 7)) 2944, 1585, 1,52 2H); 1.90 2H); 1547, 1507, 2.40 6H) 3.80 4H); 43 N CCl CH Oil 1360, 1260, CDC1 3 4.0 2H, J=4, 6.45 984 (film) 1H, J=4, 7.30 (d, 1H, J=4, 8.29 (d ,2H, J=4.8) 2390, 1589, 1.62 2H); 1,88 21); 1545, 1495, 2.45 6H); 3.81 7H1); 1360, 1247, 4,16 2H, J=6, 6.46 44 N CI Me-O CH 79- 983, 835, CDC1 3 1H, J=4, 6,9 2H1, 82°C 799 (KBr) J=4, 7.4 2H, J=4, 7.55 1H); 7,7 (s, 1H); 8.28 2H, J=2, 4) TABLE I (continued) -N N- (CHZ) 4 N Z:rR -N i Z2 Example IZ 1 Z 2 R3 Z 4 M.P. 1 IR cm- NM 'H-NMR(100 MHz), 8, J=Hz I I I I I 2946, 1586, 1, 6 (in, 2 19 (in, 2H); 1549, 1485, 2,4 6 (mn, 6H) 3, 8 (in, 4 H); C 1395, 1257, 4, 16 2H, J= 6, 8 6, 4C, N CH -CH 108- 982, 951, CDC1 3 1H., J=4, 7) 7.36 4H, 110*C 830 (KBr) J=1, 3) 7.7 2H, J=6, 2); 28 2H-, J=2, 3) F -2943, 1586, 1. 55 (mn, 2H1); 1. 80 (mn, 2H); 1487, 1359, 2. 45 (mn, 6H) 3, 81 4H1, N1260, 984, J=5) 4,.12 2H1, 6,25 4 6 N CH CH Oil '726 (film) CDC13 (2H1, t, 6,44 (1H1, t, 1493, 1446, (mn, 4H1); 3.8 (mn, 611); 4.2 (t, \1359, 1258, 2H, J=6, 6, 7 111, J=4, 47 N CH -CH 39- 983, 760 CDC13 7.2-7,7 (ains. compi. 511); 4 2 *C (film) 8,0 111); 8, 2 111); 8A4 2H1, J=2, 3) TABLE I (continued) N N- (CHZ) 4

-N

N

Z

Exmpe 1 R3 4MP- IRcm1 NMR IH'--NNR(100 MHz), 8,J=Hz Examle 1

Z

2

Z

4 n~p. IR m 1 solvent 1 2942, 1585, 1 m H ,9 2H 1547, 1485,2.5(,6)38(m 1359, 1260, 4H1); 4.2 211, J=6, 8); 48 N CPh it CPh 80- 983, 763, CDC1 3 6,4 lH, J=4, 6,6 82-C 697 (film) Cs. 1H); 7.2-7.4 (abs.

cornpl. 811); 7,8 (in, 2H1); 2H1, J=2, 4) r -2931, 1584, 1.45 Cm, 2H1); 1,85 (m, 1548, 1490, 2H1); 2,40 (mn, 6H1); 3,.80 49 N CH S0 2 -NIH- CHI 92- 1358, 1167, CDC1 3 (mn, 4H1); 4,.0 2H1, 3=6, 9 5e0C 983 (KBr) 6,47 Ct, 111, J=4, 6); 1H1); 7.5 (mn, 611); 211, 2 J=4, 6) 2943, 1585, 1.5 Cm, 211); 1.85 (in, 1548, 1446, 211); 2,28 (in, 9H1); 3.8 N CHI Me S0 2 -Nii-- C11 100- 1360, 1161, CDC1 3 (mn, 411); 1,0 211) 110 0 C 984 (KBr) 6.45 1H1, J=4, 7- 7 (5 m, 6H1); 8.27 (d, 2H, J=4, 7) TABLE I (continued) N /N 7 ./R3

N-(CH

2 4

-N

N/ .Z 2 N Z\ Example Zi Z 2

R

3

Z

4 m.p. IR cm 1 NMR H-NMR(100 MHz), 8, J=Hz solvent 2941, 1586, 0.91 3H, J=6, 1,45 1548, 1448, 4H); 1.85 (min, 4H); 2.40 1360, 1146, 6H); 3.0 2H); 3.80 51 N CH n-Bu-S0 2 -NH- CH Oil 984, 755 CDC1 3 4H); 4.11 2H, J=6, (film) 6,5 1H, J=4, 7. 4 2H); 7,5 1H); 8.3 (d, 2H, J=4, 7) 2940, 1586, 1,0 3H, J=7, 1.55 (m, 1540, 1447, 2H); 1, 9 4H) 2,45 (n, 1360, 1146, 6H); 3.0 2H, J=7, 3,8 52 N C11 n-Pr-SO 2 -Nii- CH Oil 984, 755 CDC1 3 4H); 4,1 2H, J=6, 4); (film) 6,46 1H, J=4, 7.35 2H); 7.5 1H); 8. 3 (d, J=4, 7) 2943, 1586, 1.36 5H); 1.9 2H); 1548, 1447, 2. 45 6H) 3,0 2H); 1360, 1146, 3, 6 4H); 4, 1 2H, J=6, 53 N CH Et-S0 2 -NH- CH oil 984, 754 CDC1 3 6.45 1H, J=4, 7); (film) 7,39 1IH); 7,51 IH); 8.3 -2H, J=4, 7) TABLE I (continued)

/\N

>-N

N

N- (CH) 4

-N

z 2 2

"Z

Eamle 1 2 R3 Z 4 m.p. IR cm 1 NMR 'H-NMR(100 MHz), 6, J=Hz solvent' 1 2939, 1586, 1.7 4H) 2.3-3,0 (abs.

1547, 1448, compl. 18H); 3.8 4H); 54 N CMe -S0 2 -N-Me 2 CMe Oil 1360, 1290, CDC1 3 4,0 2H, J=6, 9B3, 951, IH, J=4, 8.2 (d, (film) 21H, J=2, 3135, 2943, 1. 6 2H) 1,9 2H) 1586, 1512, 2,3-2,7 (abs. compl. 13H); 1357, 1328, 3,8 4H) 4, 2 211H, N CH -S0 2 -N-Me 2 CH 100-102°C 1156, 982, CDC1 3 J=6, 6,4 IH, J=4, 728 (KBr) 7,75 1H, J=4, 4); 2H, J=2, 4) 3330, 1590, 1,95 2H); 3,3 6H) 1556, 1449, 4,0 5H); 4,27 211, 56 N CH -S0 3 -H CH 230-235°C 1220, 1178, D 2 0 J=6, 6.8 1H, J=4, 1049, 971, 8) 7, 8 1H) 8. 0 (s, (KBr) 1H); 8,43 2H, J=2, 4) 2940, 1585, 1, 6 2H) 1,8 (min, 211); 1500, 1360, 2,5 6H) 3,80 6H); 57 CH N H CH oil 1260, 975 CDC13 6,5 1H, J=4, 6,9 (film) IH) 7, 1 1H) 7, IH) 8, 4 2H, J=4, 7) TABLE I (continued) N 4 R N N- (CH 2 4 ZI ~Z 2 Example j Z 1 ZR3Z 4 M. P. IR CM- 1 NNR 1 H-NMR(100 MHz), 8, J=H-z 2941, 1586, 1.72 (in, 4H); 2.37 (s, 1547, 1499, 3H); 2, 44 (in, 6H) 3. 58 C~e N H CH Oil 1359, 1259, CDC1 3 (mn, 6H) 6,45 IH, 983 (film) J=4, 6,85 2Hf, IJ=4, 8.27 2H, 7) 2946, 1584, 1,4-2,1 (abs.compl. 4H); 1543, 1492, 2.46 (in, 6H); 3.86 (mn, 59 CH N Cl CCI 69-710C 1359, 1254, CDC1 3 6H); 6,47 1H, J=4, 983, 797 7) 7. 38 1H)fl; 8. 29 r) 2H, J=41 7) TABLE I (continued) -N N-CH 2 4

-N

2 zI Example Z Z 2

R

3

Z

4

R

7 8 R9 m.p. IR cm-1I NMR H-NMR(100 MHz), J=Hz solvent 2833, 1511, 1.43 2H); 1.78 (m, 1448, 1247, 2H); 1,71-2.48 (a.c.

1029,1 979, 6H); 2,93-3,02 4H); N CH Cl CH H H MeO- 76- 824 (KBr) DMSO-d 6 3.67 3H); 4,09 (t, 77C J=6, 8Hz, 2H); 6.83 (s, 4H); 7.52 1H); 7.98 1H) 2940, 2818, 1.33-1.87 4H); 1512, 1457, 2,32 3H); 2.41-2.51 1245, 1183, 6H); 2,82-3.0 (m, 61 CMe N Cl CCI H H MeO- 73- 1036, 826 DMSO-d 6 4H); 3,67 3H); 3,93 0 C (KBr) J=7, 2Hz, 2H); 6.83 4H); 2941, 2816, 1.39 2H); 1.77 (m, 1500, 1450, 2H); 2.22-2.45 (a.c.

1241, 749 6H); 2.92 411); 3.76 62 N CH Cl CH MeO- H H Oil (film) DMSO-d 6 3H); 4,07 J=6, OHz, 2H); 6.87 4H); 7,51 1H); 7.95 (s, 1H) TABLE I (continued) R3 Rg 'N N- (CH) 4 Rg

RI

Example Zl Z2 R3 Z4 R7 R8 R 9 m.p. IR cm-1 NMR 1 H-NMR(100 MHz), 6, J=Hz 2943, 2820, 1.43-1.60 4H); 1502, 1405, 2.33 3H); 2,40-2.50 1241, 1030, 6H); 2,95 (m, 63 CMe N C1 CCI MeO- H H 82- 746 (KBr) DMSO-d 6 4H); 3,76 3H); 3.93 83°C J=7, OHz, 2H); 6.89 4H) I r1 1 a J I 1601, 1496, 1203, 970 1578, 1451, 1171, film) HeO- Oil CDC13 J m, I .I M, 2H); 2,28-2.56 (a.c.

6H); 3,16 4H); 3.7 3H); 4.05 J=7, OHz, 2H); 6.4 3H); 7.15 1H); 7,34 (s, 1H); 7.40 1H) 1.50-1.80 4H); 2.31-2,61 6H); 3,06 4H); 3.74 (s, 3H); 3.81 J=7, OHz, 2H); 6.1 2H); 6, 6 2H); 6,04 4H) i i- I I I

I

CH

2943, 2815, 1512, 1455, 1244, 1037, 823, 724 (.film) MeO- oil CDC13 r I I I= A 2 TABLE I (continued) R3 N NN-(CH 4

-N

1 Z 2 n rExapqe~ P2T MP-2940, 2814, Slet1,50-1,85 4H); 1500 11451, 2,33-2,66 6H1); 1281, 1241, 3,10 (in, 4H1); 3,84- 66 CH C11 H CH MeO- If H Oil 1028, 743, CDClj 3,96 5H1); 6,12 723 (film) J=2Hz., 210); 6,65 J=2Hz, 211); 6, 93 (in, 4H1) 2943, 2817, 1.41-1.89 4H1); 1600, 1501, 2,37 J=7, 3Hz, 211); 1235, -759, 2.50-2.60 411); 67 CHI CH H CH H1 if H oil 723, 692 CDC1 3 3,18 (mn, 411); 3.89 (t, (film) J=6, 9Hz, 211); 6, 13 (t, J=2, 0Hz, 211); 6,64 (t, J=2, 0Hz, 211); 6,83- 7.33 511) TABLE I (continued)

R

9 N H 2 N Z (R 2 R3 Z4 R 1 R- .P Rcm NR-NMR (100 MHz), -xml =i Z solvent J=Hz 2942, 2819, 1,4 7 (mn, 2 H) 1. 84 (mn, 1600, 1500, 2,35 Mt J=7, 2Hz, 1450, 1 81, 2H); 2,52 (in, 4H); 3.16 r 68 N CH Cl CH if H H 58- 1311, 1240, CDC1 3 (in, 4H) 4. 04 J=6, 61-C 1140, 966, .8Hz, 2H); 6.75-6. 94 756 (KBr) a.c. 3H); 7,16 H); 7,23 1H); 7,35 (d, J=7, 4Hz, 2H) -2944, 2819, 1,43-1,87 4H); 1600, 1532, 2.33 3H) 2. 38-2, 69 CMe N Cl CCI H H H oil 1503, 1453, CDCI 3 6H) 3.17 (mn, H); 1404, 1244, 3,.83 3=7Hz, 2H) 1143, 759, 6,9 7.24 (in, 692 (film) 2H]) 2943, 2817, 1.40 (mn, 2H); 1.78 (in, 1587, 1480, 2H); 2.2-2,6 611); N CH CHI CHI CI H H oil 1443, 1231, DMSO-d 6 2. 95 (mn, 4H); 4,08 (t, 1040, 971, J=6, 5Hz, 2H) 6,95- 751, 612 .7.41 7,50 (film) s, 7.97 11]) TABLE I (continued) R N N- (CH)4 N Rg RI Example Z 1

Z

2 R3 Z 4 R7 Rg R m.p. IR cm- 1 NMR 'H-NMR (100 MHz), 8, J=Hz solvent 2936, 2818, 1,3-1,8 4H); 2,32 1587, 1531, 3H); 2.35-2,70 (a.c.

1480, 1359, 6H); 2,96 4H); 3,94 (t, 71 CMe N Cl CC1 Cl H H 89- 1243, 1229, CDC13 J=7, 2Hz, 2H); 6.90-7.50 91°C 1036, 1016, aH) (KBr) 2944, 2820, 1.3-1,70 2H); 1,70-2,10 1594, 1564, 2H); 2.39 J=7, 4Hz, 1487, 1451, 2H); 2,59 4H); 3,17 (m, 72 N CH Cl CH H Cl H Oil 1433, 1384, CDC1 3 4H); 4.09 J=4Hz, 2H); 1239, 987, 6.6-6.9 3H); 7,15 (t, 980 (film) J=8, OHz, 1H); 7.37 (s, 1H); 7.4 1H) 2956, 2848, 1.45-1,80 4H); 2,37 2219, 1593, 3H) 2,20-2,70 (a.c.

1488, 1240, 6H); 3.23 4H); 3.88 (t, 73 CMe N Cl CCl CN H H 80' 1232, 1010, CDC13 J=7, 1Hz, 2H); 6,90-7,06 (Dec) 765 (KBr) 2H); 7,30-7.60 (a.c.

2H) TABLE I (continued) R N N

R

Z--(CH

2 2 Re RI Example Z 1 Z2 R 4 R- 7

R

8

P

9 tM.P.~ IR cr&' ~NMR I1H-NMR(l0O MHz), 8, J=Hz 2944, 2B22, 1,30-1,80 4H); 1501, 11406, 2. 35 3H); 2,20-2,70 74 Ge N 1l CCl F H H oil 1241, 1141, CDC1 3 6K); 3.10 (in, 754 (film) 4H); 3.87 J=7Hz, 2H); 6,70-7.07 (a.c.

4H) -2948, 2823, 1.50 (mn, 2H); 1.86 (mn, 2219, 1596, 2H) 2,43 J=7Hz, N CH CI CH CN H H 590 1488, 1447, CDC1 3 2H); 2,63 (in, 4H1); 3.23 (dec) 1376, 1231, 4H) 4. 11 J=6, 971, 762 8Hz, 2H); 6.80-7.10 (film) 2H); '7.25-7.65 4H) 2946, 2821, 1.35-1.75 4H); 1609, 1450, 2,35 3H); 2.30-2.65 76 C.Me N cl CClI H CF3 H oil 1357, 1319, CDC13 c. 6H) 3. 22 (mn, l 1245, 1163, 4K); 3.87 J=7, lz 1122, 697 6.95-7.10 (a.c.

t(film) 3H); 7.32 (mn, TABLE I (continued)

R

9 N N- (CH 2 4 -N

R

Z z 2 R a z

I

Exml i Z2 R 3 Z4 R 7

R

8

R

9 mp I R cm- NNM 'H-NR(100 MHz), 8, J=Hz 2941, 2821, 1. 49 (in, 2H) 1. 89 (in, 1610, 1450, 211); 2.38 J=7, 2Hz, 1357, 1319, 2H); 2.53 (in, 4H1); 3,21 77 N CH Ci. CH H CF 3 H Oil 1163, 1123, CDC1 3 (in, 4H1); 4,08 J=6, 696 (film) 8Hz, 2H); 6.95-7.12 3H1); 7,20-7.45 (in, 3H1(8 =7,36 s ,IH; =7.40 s, 1H]) 2944, 2820, 1,50 (in, 2H); 1,89 (in, 1501, 1451, 2H); 2,41 J=7, 2Hiz, 1239, 971, 21H) 2, 59 (in, 4H1); 3,10 78 N CH CI CH F H H oil 753 (film) CDC1 3 (in, 4H1); 4,09 J=6, 9Hz); 6,80-7,10 (a.c.

411); 7,37 1H1); 7,40 6 111); TABLE I (continued) Ar-N N- (CH 2 4 N Z4

R

Z,

,-Z

Example 1 z I 2

Z

4 Ar 3r.. I m solvent I 1--NR(l 00 MHz),5 J=Hz, 2943, 2815, 1.50 (in, 2H); 1,85 (in, 1493, 1451, 2H); 2. 45 3=7, 2Hz, S N1423, 1383, 2H); 2,60 J=4, 7Hz, 79 N CH CHI c1 Oil 1307, 1261, CDC1 3 4H); 3. 53 t, J=5, 0Hz, 970, 739, 4H1); 4,07 J=7, 0Hz, 613 (film) 2H); 7,35 (in, 4H); 7,85 Cm, 2H) 2944I, 2816, 1.55-1,85 4H); N1533, 1493, 2, 34-2. 49 5H) S 1422, 1380, 2,62 J=4, 7Hz, 41fI) C~e N CCI Cl oil 1280, 1246, CDC13 3.53 J=5, 0Hz, 4H); 1139, 1017, 3,84 J=7, 0Hz, 211 754, 665 7,37 (in, 2H); 7.83 (in, C(film) -2H) TABLE I (continued) Ar -N N- (CH 2 4 -N A

R

"z 'H-NMR (100 MHz), 8, J=Hz 1,55 (in, 2H1); 1.97 (mn, 211); 2,45 J=7, 3 2H1); 2,64 4H); 3,55 411); 4.22 J=6, 9Hz, 2H1); 7,35 7(8m, J=817,6 11); 7,90 J=BHz, 1H1); 7,95 1H1); 8,08 (s, 1H1) 1.56 211); 1,96 (mn, 2H1); 2.42 J=7, 1Hz, 2H1); 2,61 4H1); 3.53 4H1); 4.19 J=7, 0Hz, 2H) 7.10-7,50 511); 7,70-7,90 4H1) TABLE I (continued) R3 Ar -N N- (CH) 4

-N

1 IP. crif' Examplel Zj Z 2 R3 IR cm-1 solvent I =HzI I o r I 1.57 (in, 2H); 1.90 3 r

/C

84, 60C 126, 1311, (KBr) 1365, 950 C DC 13 1.5, 2(m, 2.45 1i,9 6(m) 3.80 2.45 4(m, J6); 7.40 (t,H .29 211) L I 1585, 1525, I I I I CH C1 Br

C

1495, 1364 (KBr) 85- 86*C C DC 13 (mn, 2H1); 2.40 (mn, 611); 3.76 (mn, 4H1); 4.08 (mn, 2H1); 7.4 2H1, J=6, 9); 8.25 211) I I. 39 The examples which follow illustrate the properties of a few derivatives which fall within the scope of the present invention.

I. COMPULSIVE OBSESSIVE DISORDER Given that serotonin (5-HT) is believed to be involved in the pathophysiology of affective disorders, pharmacological stimulation paradigms have largely been used to determine the "in vivo" dynamics of the function of serotonin in compulsive obsessive disorder, inter alia. The 5-HT precursors (a-tryptophan and tryptophan), the 5-HT uptake inhibitors and/or liberators (DL-fenfluramine) and the agonists which act directly on (m-CPP, MK-212 and buspirone) have attracted considerable attention as possible probes of the functional state of the central nervous system of 5-HT in several affective disorders, although both the specificity for the 5-HT system in general and the selectivity for the receptor subtypes in particular continue to be contested (Murphy et al.: J. Clin. Psychiatry 47: 9-15, 1986; Murphy et al.: Br. K. Psychiatry 155 (suppl. 8): 15-24, 1989; Van de Kar, Neurosci. Biobehav. Rev.

13: 237-246, 1989).

Moreover, there is increasing evidence that the ligands buspirone, gepirone and ipsapirone are anxiolytic active agents, possibly with antiobsessive properties, although their mechanism of action is not very clear (Lesch et al.: Life Sci. 46: 1271-1277, 1990).

During the study of the anxiolytic activity of agents with affinity for the 5-HT, receptor, one of the most representative tests is that which determines the avoidance behaviour of mice in a box with a very brightly lit compartment, light box, and the other dark (light/dark box) (Costall et al. J. Pharmacol. Exp.

Ther. 262 90-98, 1992).

The mice are placed in the lit compartment which becomes their aversion and provokes in them a state of anxiety. This provokes a fleeing reaction towards the dark compartment, which may be associated with compulsive 40 obsessive behaviour. The results obtained (see table) demonstrate that lesopitron, at all the test doses, delays the appearance of the compulsive obsessive behaviour of movement to the dark area since the delay time increases clearly.

Treatment Delay in passing from lit area to dark area Controls (vehicle) 10 seconds Lesopitron 0.0001 mg/kg, ip 15 seconds Lesopitron 0.01 mg/kg, ip 20 seconds Lesopitron 0.5 mg/kg, ip 24 seconds II. SLEEP APNOEA SYNDROME Sleep apnoea syndrome comprises a series of disorders of different gravity. Sleep apnoea is classified as obstructive, central or mixed, depending on the presence or absence of respiratory efforts during periods in which the airflow is stopped. Obstructive and mixed apnoeas are the most common. They exhibit the syndrome of obstructive sleep apnoea, in which recurrent and sporadic collapses of the upper respiratory pathways are observed during sleep. If the collapse is complete, there is no circulation of air through the nose and the mouth, and respiration stops. The usual result is partial wakening from sleep and a return to normal respiration. In several cases, the patient does not remember these episodes of apnoea, but he feels tired and sleepy during the day, for no apparent reason. These episodes of recurrent apnoea with hypoxaemia and fragmented sleep may lead to serious neurological and heart consequences.

Hitherto, the pharmacological treatment of sleep apnoea syndrome has met with little success. Recently, a few-publications have reported the possible usefulnes of buspirone, a 5-HT, agonist, in sleep apnoea disorders (Mendelson et al., J. Clin. Psychopharmacol. 1991 11 In order to determine the action of lesopitron on 41 respiration and sleep, and consequently the possible use of this agent in sleep apnoea syndrome, its effect was studied on the respiration of rats, following the work carried out in this respect on buspirone (Mendelson et al., Am. Rev. Respir. Dis. 14(6): 1527-1530, 1990).

The results obtained demonstrate that at doses of and 30 mg/kg, lesopitron gives rise to a significant increase in the breathing rate, as well as to pulmonary ventilation in anaesthetized rats.

42 Respiratory action of lesopitron on rats anaesthetized with uretane.

Lesopitron dose Pulmonary venti- Increase in the (mg/kg, lation (increase breathing rate maxima) (inhalations/ minute 0.3 10 9 1 20 3 20 18 22 44 23 LO The electroencephalographic study of the rats' sleep demonstrated that at 5 mg/kg lesopitron significantly increases the sleep latency at the same time as it decreases the total sleeping time, that is to say that it increases the period of wakefulness.

Electroencephalographic study of sleep in rats.

Group Sleep latency (min) Period of wakefulness (min) no REM REM Control 32 3 62 6 90 (vehicle) Lesopitron 71 4 194 130 4 (5 mg/kg, s.c.) Summarizing the results obtained, it may be affirmed that lesopitron may be a respiratory stimulant with persistent effects during sleep. It is consequently indicated in the treatment of sleep apnoea syndrome.

III SEXUAL DYSFUNCTION The aetiology of sexual dysfunction may include psychological factors, interpersonal and circumstantial reasons, physical factors and also secondary effects of 43 pharmacological agents.

Given that sexual dysfunction may be due to a wide variety of these underlying causes, which may range from those which are purely psychogenic to entirely physical causes, it would not be realistic to hope that a single mode of treatment could become effective in all cases. In the usual clinical practices, sexual dysfunction is treated by determining the underlying causes and by treating them whenever possible. In several cases, identification of the underlying causes of sexual dysfunction in men and women is very complex, or even, it cannot be determined with certainty. The psychopharmacological treatment of sexual dysfunction is currently in its infancy. The use of medicaments to treat sexual dysfunction has met with little success, which is demonstrated by the absence_ of a treatment which is widely accepted and recognized for this use.

Activation of the 5-HT, receptors appears to facilitate the sexual behaviour of male rats, given that 8-OH-DPAT increases the number of sexual encounters and decreases the ejaculation latency (Murphy et el.: J.

Clin. Psychiatry 47: 9-15, 1986; Murphy et al.: Br. K.

Psychiatry 155 (suppl. 15-24, 1989). Similar effects have been found with other 5-HT, receptor-selective products such as buspirone, gepirone or ipsapirone.

However, it is not known-if the effect of 5-HT, agonists in the sexual behaviour of male and female rats is provoked, either by stimulation of the 5-HT3 autoreceptors by these products this reduces the synthesis of 5-HT and causes the serotoninergic function to decrease or by stimulation of the post-synaptically localized receptors.

In order to demonstrate the capacity of lesopitron to improve sexual dysfunction, its action on the sexual behaviour oi male rats was evaluated. In this respect, the methodology described by M.M. Foreman et al.

Pharmacol. Exp. Ther. 270 1270-1281 (1994)) was followed. The main indicator used to evaluate the action of the product was the EL (time required to reach 44 ejaculation, or ejaculation latency after intromission).

Dose of lesopitron inhibition in ejaculation (mg/kg, subcutaneous) latency relative to the control group 0.1 40 1 60 10 70 EL for the group treated with vehicle: 745 seconds The results obtained with lesopitron demonstrate the activity of the product in facilitating the sexual behaviour of rats.

IV. EMESIS The compounds of the invention were studied with regard to their effects on emesis in ferrets according to a method described by Costall et al. (Neuropharmacology, 1986, 25, 959-961).

Ferrets of both sexes (0.7 1.4 kg) were caged individually at 21 1 0 C and were fed normally. The compound of Example 32 or a vehicle was then administered to them subcutaneously as a pretreatment of 15 minutes before the administration of cisplatin (10 mg/kg i.v. via a fixed jugular cannula). The animals were observed at the start of the emesis and afterwards, for 240 minutes.

The emesis was characterized by rhythmic abdominal contractions, either associated with the expulsion of solid or liquid matter (that is to say vomiting) or not associated with the passage of matter through the mouth (nausea). The number of episodes and the nausea or the vomiting were recorded.

The compound of Example 32 is capable of antagonizing the emesis induced by cisplatin (Figure 1).

Figure 1: The compound of Example 32 is capable of antagonizing the emesis induced by cisplatin in fer- 45 rets. The animals received a vehicle n 7) or the compound of Example 32 (0.05 0.5 mg/kg n 4) for each level of dose, 15 minutes before the intravenous administration of cisplatin (10 mg/kg). The animals were observed for 240 minutes. A significant difference when compared with V is indicated sP 0.05 (Mann-Whitney U test).

In human therapy, the dose of administration is obviously a function of the seriousness of the complaint to be treated. It will generally be between about 5 and about 100 mg/day. The derivatives of the invention will be administered, for example, in the form of tablets or gelatin capsules or alternatively intravenously. Two specific pharmaceutical forms are shown below, by way of example.

Example of a tablet formulation Compound of Example 32 20 mg Lactose 50 mg Microcrystalline cellulose 20 mg Povidone 5 mg Pregelatinized starch 3 mg Colloidal silica dioxide 1 mg Magnesium stearate 1 mg Tablet weight 100 mg Example of a gelatin capsule formulation Compound of Example 32 20 mg Polyoxyethylenated glycerol 125 mg Glyceryl behenate 5 mg 150 mg Excipient: soft gelatin q.s.

Example of an injection ampule formulation Compound of Example 32 4 mg 8 mg Sodium chloride 15 mg 30 mg Water for injection q.s. 2 ml 4 ml 46 Given the advantageous pharmacological properties associated with the compounds of general formula I, the present invention covers the use of these compounds as medicaments, the pharmaceutical compositions containing them and their use for the manufacture of medicaments for use in the treatment of compulsive obsessive disorders, sleep apnoea syndrome, sexual dysfunctions, emesis and travel sickness, in particular for the manufacture of antiobsessive agents, agents for preventing sleep apnoea syndrome, agents which facilitate sexual behaviour, and antiemetic and antinausea agents.

Claims (66)

1. Use of compounds of general formula I "I R3 Ar- (CH2)4 -Nl in which Ar represents a nitrogenous or non-nitrogenous aromatic radical chosen from variously substituted aryls, variously substituted 2-pyrimidine, and 3-(1,2- benzisothiazole), Z1 represents a nitrogen atom or a substituted or unsubstituted carbon atom which may be represented by: C-R,, Z2 represents a nitrogen atom or a substituted or unsubstituted carbon atom which may be represented by: C-R 2 Z4 represents a nitrogen atom or a substituted or unsubstituted carbon atom which may be represented by: C-R 4 and R 1 R 2 R 3 and R 4 which are identical or different and may also form part of i another aromatic or non-aromatic ring, represent a hydrogen atom, a halogen, a C 1 -C 6 alkyl (as hereinbefore defined) radical, a nitro radical, a hydroxyl radical, a C,-C 6 alkoxy radical (as hereinbefore defined), a cyano radical, a hydroxycarbonyl radical, a C,-C 6 alkoxycarbonyl radical, an aryl or substituted 20 aryl radical, a sulphonic radical, a sulphonamido radical, an aminocarbonyl radical, which may or may not be substituted on the amino group, an amino or substituted amino radical, and their therapeutically acceptable salts, for the preparation of a medicament for use in the treatment of compulsive obsessive disorders, sleep apnoea syndrome, sexual dysfunctions, emesis induced by cisplatin and travel sickness in mammals, including man.

2. Use according to Claim 1, wherein the compounds of general formula I are selected from the following group: 1. 1 -{4-[4-(2-pyrimidinyl)-1 -piperazinyl]butyl}pyrrole, 2. 1-{4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl}carbazole, H:Xapps\winword\JENNnennyM\eil\spemkiA1 3764-97.DOC -48

3. (2-pyrimidilyl) -1-piperazinyllbutyl~ildole,

4. 2,3-diphenyl-1-{4- (2-pyrimidinyl) -1-piperazinyl] butyl) indole, 4-abxmd--4[-2-yiiiy)lppr azinyljbutyl}-1H-pyrazole,

6. 4-carboxy-1-{4- (2-pyrimidinyl) -1-piperazinyl] butyl) -1H-pyrazole,

7. 3-methyl-5-trifluoromethyl-1-{4- (2-pyrimidinyl) 1-piperazinyl] butyl) -1H-pyrazole,

8. 4,5-diphenyl-1-{4- (2-pyrimidiny1)piperazill- butyl) -1H-imidazole,

9. 2,,-rpey--4 4 2prmdnl 1ppr azinyl] butyl}-1H-imidazole, 4,5-dipheny1-2-methy1-1-{4-[4-(2-pyriidilyl)- 1-piperazinyl] butyl}-1H-imidazole, 1-piperazinyl] butyl) -1H-ixnidazole, butyl) -1H-imidazole,

13. 2-phenyl-1-{4- (2-pyrimidinyl) -1-piperazinyl] butyl) H- imidazole,

14. 4-methoxycarbonyl-1-{4- (2-pyrimidinyl) -1-piper- azinyl] butyl}-1H-imidazole, 4-phenyl-1-{4- (2-pyrimidinyl) -1-piperazill butyl)-1H-imidazole,

16. (2-pyrimidi-nyl) -i-piperazinyllbutyl}-1H- benzimidazole, imidazo pyridine,

18. [4-(2-pyrimidinyl)-1-piperaziflbutyl)-1H- imidazo 5-b] pyridine, benzotriazole, 2-chloro-1-{4- [4-(2-pyrimidiny1)-1-piperazill- -butyl}-1H-benz. nidazole, 1,2,4- triazole,

22. [4-(2-pyrimidiny1)-1-piperazifl1butyl)2H- benzotriazole, 49

23. 2-methyl-1-{4- (2-pyrimaidinyl) -1-piperazinyl] butyl} -1H-benzimidazole,

24. 5,6-dimethyl-1-{4- (2-pyrimidinyl) -1-piperazinyl] butyl) -1H-benzimidazole,

25. (2-pyrimidinl) 1-piperazinyl]buty)-lH- pyrazole,

26. 3,5-dimethyl-1-{4-[4- (2-pyrimidinyl) -1-piperazinyl] butyl) -1H-pyrazole, 1-piperazinyl] butyl) -1H-pyrazole,

28. 4-methyl-1-{4- (2-pyrimidinyl) -1-piperazinyl] butyl) -1H-pyrazole,

29. (2-pyrimidinyl) -1-piperazinyllbutyl}-1H- imidazole,

30. 4-bromo-3,5-dimethyl-1-{4-[4-(2-pyrimidilyl)- 1-piperazinyl] butyl}-1H-pyrazole,

31. 4-nitro-1-{4- (2-pyrimidinyl) -1-piperazill]- butyl) -1H-pyrazole,

32. 4-chloro-1-{4- (2-pyrimidinyl) -1-piperazinyl] butyl) -1H-pyrazole dihydrochioride,

33. 4-ethoxycarbofyll{4 (2-pyrimidinyl) -1-piper- azinyl] butyl}-1H-pyrazole,

34. 3-methyl-5-pheflyl-1-{4- (2-pyrimidinyl) -1-piper- azinyl] butyl}-1H-pyrazole,

35. 4-bromo-1-{4- (2-pyrimidiny1) -1-piperazilJ- butyl}-1H-pyrazole,

36. 4-cyano-1-{4- (2-pyrimidil) -1-piperazill]- butyll}- 1H-pyrazole,

37. 4-fluoro-l-{4- (2-pyrimidinyl) -1-piperazill butyl}-1H-pyrazolei

38. 4-amino--1-{4- (2-pyrimidinyl) -1-piperazill]- butyl) H-pyrazole.,

39. 4-methylsulphoflamido-1-{4- (2-pyrimidinyl) 1-piperazinyl] butyl}-1H-pyrazole,

40.- 4-benzaxnido-1-{4- (2-pyrimid. .yl) -1-piperazinyl] butyl) H-pyrazole,

41. 4-acetainido-1-{4- (2-pyrimidinyl) -1-piperazinyl] butyl) -1H-pyrazole,

42. 4-(2-butyl)amifolO--{4- (2-pyrimidinyl) -1-piper- azinyl] butyl)-1H-pyrazole,

43. 3-chloro-4-fluoro-1-{4- (2-pyrimidinyl) -1-piper- azinyl] butyl}-1H-pyrazole,

44. 4 -methoxyphel) pyrimidil) 1-piperazinyl] butyl) -1H-pyrazole, 4 -chlorophenyl) -1 -pyrimidil) 1-piperazinyl] butyl) -1H-pyrazole, azinyl] butyl}-1H-pyrazole,

47. 4-phenyl-1-{4- (2-pyrimidinyl) -1-piperazinyl] butyl) -1H-pyrazole,

48. 3,5-diphenyl-1-{4- (2-pyrimidinyl)-1-piperazinyl] butyl) -1H-pyrazole,

49. 4 -phenylsulphamoyl- (2-pyrimidilyl) 1-piperazinyl] butyl) -1H-pyrazole, 4- (4-methylbenzene) sulphamoyl-1-{4- (2-pyrimid- inyl) -1-piperazinyl] butyl) -1H-pyrazole,

51. 4-butylsulphanioyl-1-{4- (2-pyrimidinyl) -1-piper- azinyl] butyl}-1H-pyrazole,

52. 4 -propyl sulphamoyl -1 Pyrimidilyl) 1-piperazinyl] butyl)-1H-pyrazole,

53. 4-ethylsulphamoyl-1-{4- (2-pyrimidinyl) -1-piper- azinyl] butyl) H-pyrazole,

54. 3,5-dimethy1-4-(N,N-dimethysuphoflaido)-l- pyrazole, 4-N-methylsulphamoyl-1-{4- (2-pyrimidinyl) 1-piperazinyl] butyl}-1H-pyrazole,

56. 4-sulphonic-1-{4- (2-pyrimidinyl) -1-piperazinyl] butyl) -1H-pyrazole,

57. 1-{4-[4-(2-pyrimidinyl)-1-piperazilbuty1}- 1 -imidazole,

58. 2-methyl-1-{4- (2-pyrimidinyl) -1-piperazinyl] -butyl}-1H-imidazole,

59. 4,5-dichloro-1-{4- (2-pyrimidinyl) -1-piperazinyl] butyl) -1H-imidazole, 4-chloro-1-{4- (4-methoxyphenyl) -1-piperazinyl] _____butyl)-1H-pyrazole, I. 51

61. 4,5-dichloro-2-methyll{4- (4-methoxyphenyl) 1-piperazinyl] butyl}-1H-imidazole,

62.' 4-chloro-1-{4- (2-methoxyphenyl) -1-piperazinyl] butyl} -1H-pyrazole,

63. 4,-ihoo2mty--4 4 2mtoyhnl 1-piperazinyl] butyl}-1H-imidazole,

64. 4-chloro--1-{4- (3-methoxyphenyl) -1-piperazilyl] butyl) -1H-pyrazole, 1 4- (4 -me thoxyphenyl) 1-piperaz inyl Ibutyl Ipyr role,

66. (2-methoxyphenyl) -1-piperazinyllbutyl~pyr- role,

67. (phenyl) -1-piperazinyl]buty11pyrrole,

68. 4 -chl oro- 1 (phenyl) -i1-piperaz inyl Ibu~tyl)}-1H pyrazole,

69. 4,5dclr--ehll{-[-(hnl 1ppr azinyl] butyl)-1H-imidazole, 4-chloro-1-{4- (2-chiorophelyl) -1- piperazinyl] butyl) -1H-pyrazole,

71. 4, 5-dichloro-2-methyl-1-{4- (2-chloropheyl) 1-piperazinyl] butyl}-1H-imidazole,

72. 4-chloro-1-{4- (3-chiorophelyl) -1- piperazinyl] butyll H-pyrazole,

73. 4,5-dichloro-2-methyl-1-{4-[4-(2-cyanophelyl)- 1-piperazinyl] butyl)-lH-imidazole,

74. 4, 5-dichloro-2-met-hyl-l-{4- (2-f1uorophenyl) 1-piperazinyl] butyl}-1H-imidazole, 4-chloro-1-{4- (2-cyanopheflyl) -1- piperazinyl] butyl) -1H-pyrazole,

76. 4,5-dichloro-2-methyl-1-{4-[4-(3-trifluoromethyl- phenyl) -i-piperazinyllbutyll-1H-imidazole,

77. 4-chloro-1-{4- (3-trif1uoromethylphenyl) 1-piperazinyl] butyl)-1H-pyrazole,

78. 4-chloro-1-{4-(4- (2 -fluorophenyl) -1- -piperazinyl] butyl}-1H-pyrazole,

79. 4-chloro-1-{4- (1,2-benzisothiazol-3-yl) -1-piper- azinyl] butyl}-1H-pyrazole, 4,5-dichloro-2-methyl-l-{4- (1,2-belzisothiazol- 3 -yl) -i-piperaziny1]butyl}-1H-imidazole, -52-

81. 1-{4-[4-(1,2-benzisothiazol-3-yl)-1 -piperazinyl]butyl}-1 H-1,2,4-triazole,

82. 1-{4-[4-(1,2-benzisothiazol-3-yl)-1 -piperazinyl]butyl}-1 H-benzimidazole,

83. 4-bromo-1-{4-[4-(5-bromopyrimidin-2-yl)-1-piperazinyl]butyl}-1 H-pyrazole,

84. 4-chloro-{4-[4-(5-bromopyrimidin-2-yl)-1 -piperazinyl]butyl}-1 H-pyrazole. 3. Use of 4-chloro-1-{4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl}-1H-pyrazole dihydrochloride for the preparation of a medicament for use in the treatment of compulsive obsessive disorders, sleep apnoea syndrome, sexual dysfunctions, emesis induced by cisplatin and travel sickness in mammals, including man. 4. Method of treatment of a condition selected from the group consisting of compulsive obsessive disorders, sleep apnoea syndrome, sexual dysfunctions, emesis induced by cisplatin and travel sickness in a mammal including administration of a therapeutically effective amount of a compound of general formula I -R3 Ar -N IN- (CH 2 4 Z 15 in which *0 Ar represents a nitrogenous or non-nitrogenous aromatic radical chosen from variously substituted aryls, variously substituted 2-pyrimidine, and 3-(1,2- benzisothiazole), Z1 represents a nitrogen atom or a substituted or unsubstituted carbon atom which may be represented by: C-R,, SZ2 represents a nitrogen atom or a substituted or unsubstituted carbon atom which may be represented by: C-R 2 Z4 represents a nitrogen atom or a substituted or unsubstituted carbon atom which may be represented by: C-R 4 and R 1 R 2 R 3 and R 4 which are identical or different and may also form part of another aromatic or non-aromatic ring, represent a hydrogen atom, a halogen, a C,-C 6 alkyl (as hereinbefore defined) radical, a nitro radical, a hydroxyl radical, a C 1 -C 6 alkoxy radical (as hereinbefore defined), a cyano radical, a hydroxycarbonyl radical, a C 1 -C 6 alkoxycarbonyl radical, an aryl or substituted aryl radical, a sulphonic radical, a sulphonamido radical, an H:\apps\winwordW ENNY'jennyMNeihspecnkhl 3764-97.DOC -53- aminocarbonyl radical, which may or may not be substituted on the amino group, an amino or substituted amino radical, or a therapeutically acceptable salt thereof to said mammal. A method according to claim 4 wherein said condition is compulsive obsessive disorder. 6. A method according to claim 4 wherein said condition is sleep apnoea syndrome. 7. A method according to claim 4 wherein said condition is sexual dysfunction. 8. A method according to claim 4 wherein said condition is emesis. 9. A method according to claim 4 wherein said condition is travel sickness. A method according to any one of claims 4-9 wherein said compound of general formula I is selected from the group: 1. 1-{4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl}pyrrole, 15 2. 1-{4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl}carbazole, C:\WINWORD\JENNYM\SPECNKI\13764-97.DOC 54 3. (2-pyrimidinyl) -i-PiPerazinyl]butyl}inle, 4. 2,3-diphenyl-1-{4- (2-pyrimidilyl) -l-piperazinyl] butyl }indol e, azinyllbutyl)-1H-pyrazole, 6. 4-carboxy-1-{4- (2-pyrimidinyl) -1-piperazinyl] butyl} -lH-pyrazole, 7. 3-xmethyl-5-trifluoromethy>-{-4- (2-pyrimidinyl) 1-piperazinyl) butyl)-1H-pyrazole, 8. 4,5-diphenyl-1-{4- (2-pyrimidiny1)piperazill- butyl) H- imidazole, 9. 2,,-rpey--4 4 2prmdnl 1ppr azinyl] butyl}-1H-imidazole, 4,-ihnl2mty--(-4(-yiiiy) 1-piperazinyl] butyl}-1H-imidazole, 11. 4,5-dichloro-2methy-l14[4(2-PYrimidinyl)- 1-piperazinyl] butyl)-1H-imidazole, 12 2 12. 4 priiiy)-1-pprznl 13.butyl)-1H-imidazole, 9:...:butyl} -1H-imidazole, 14. 4-methoxycarbonyl-1-{4- (2-pyrimidinyl) -1-piper- azinyl] butyl}-1H-imidazole, 4-phenyl-1-{4- (2-pyrimidinyl) -1-piperazinyl] butyl)-1H-imidazole, 16 194 4 2prmdnl 1pprznlbtl-H benzimidazole, imidazo pyridine, 18. 1-4 4 2prmdnl 1pprznlbtl-H imidazo 5-b] pyridine, 19. (2-pyrixnidinyl) -i-piperazinyJ-butyll1H- benzotriazole, 2-hool{-(-(-yimdnl 1pprznl butyl}-1H-belz. nidazole, 1, 2 ,4-triazole, 22. 2-t4-[(4-(2-pyrimidilyl) -1-piperazinyl]butyl)h2H- <<51 R~ 1 q benzotriazole, 55 23. 2-ehll{-[-(-yimdnl 1pprznl butyl) -1H-benzimidazole, 24. 5,6-dimethyl-1-{4- [4-(2-pyrimidiny1)-1-piperazil]- butyl) -1H-benzimidazole, 25. 1-4 4 2prmdnl 1pprznlbtl-H pyrazole, 26. 3,5-dimethyl-1-{4- [4-(2-pyrimidinyl)-1-piperazil]- butyl} -1H-pyrazole, 27. 3,-iehl4ntol{-4(-yiiiy) 1-piperazinyl] butyl}-1H-pyrazole, 28. 4-methyl-1-{4- (2-pyrimidinyl) -1-piperazill butyl} -1H-pyrazole, 29. 1- {4 [4 (2 -pyrimidinyl) 1 piperaziny1] butyl)}-H- imidazole, 30. 4-rm-,-iehll{-4(-yiiiy) 1-piperazinyl] butyl}-1H-pyrazole, 31. 4-ir--4 4 2prmdnl 1pprznl -1H-pyrazole, 32. 4-hool(-(-(-yimdnl 1pprznl 20 butyl}-1H-pyrazole dihydrochloride, 33. 4-ethoxycarbonyl-1-{4- (2-pyrimidinyl) -1-piper- azinyl] butyl} H-pyrazole, 34. 3-methyl-5-phefyl-1-{4- (2-pyrimidiny1) -1-piper- azinyl] butyl} -1H-pyrazole, butyl}-1H-pyrazole,- 36. 4-cyanro-1-{4- (2-pyrimidinyl) -1-piperazinyl] butyl} -1H-pyrazole, butyl}-1H.-pyrazole, butyl} -inyrletl-H-yaoe 40.- 4-benzamido-1- (2-pyrimid- iyl) -1-piperazill butyl} H-pyrazole, 41. 4-acetamido-1-{4- (2-pyrimidinyl) -1-piperazill butyl} H-pyrazole, 56 azinyl] butyl} H-pyrazole, 43. 3-chloro-4-fluoro-1-{4- (4-(2-pyrimidiflyl) 1piper- azinyl] butyl} -1H-pyrazole, 44. 4 -methoxypheny1) [4 PYrimidilyl) 1-piperazinyl] butyl}-lH-pyrazole, 4-(4-chloropheny1)-1-{4-[4-(2-pyrimidil)- 1-piperazinyl] butyl}-1H-pyrazole, 46. 4 -pyrrolyl) -1 -pyrimidiflyl)l piper- azinyllbutyl}-1H-pyrazole, 47. 4-phenyl-1-{4- (2-pyrimidinyl) -1-piperazinyl] butyll}- 1H-pyrazole, 48. 3,5-diphenyl-1-{4- [4-(2-pyrimidinyl)-l-piperazilyl] butyl} H-pyrazole, 49. 4-phenylsulphamoy--{4-4-(2-pyrimidilyl)- 1-piperazinyl] butyl})-1H-pyrazole, 4- (4-methylbenzene)sulphamoyl-1-{4- (2-pyrimid- inyl) -1-piperazinyl] butyl}-lH-pyrazole, 51. 4-butylsulphamoyl-1-{4- (2-pyrimidinyl) -1-piper- azinyilbutyl)-lH-pyrazole, 52 oy -4-4 -p r m di y 1-piperazinyl] butyl}-1H-pyrazole, 53. 4-ethylsulphamoyl-1-{4- (2-pyrimidinyl) -1-piper- azinyl] butyl} -1H-pyrazole, 54. 3, 5 -dime thy1-4 N -dime thy1sulphonami do) -1- I4(2pyrimidiny)--piperazinylbutyl)>1H- 6 *.o55 4-N-methylsulphamoyl-1-{4- [4-(2-pyrimidinyl) 1-piperazinyl] butyl} H-pyrazole, 56. 4-sulphonic-1-{4- (2-pyrimidinyl) -1-piperazinyl] butyl} -1H-pyrazole, 57. 1-{4-t4-(2-pyrimidiny1)-l-piperaziny1]buty1}- 1-imidazole, 58. 2-methy1-1-(4- (2-pyrimidifl 1piperaziyll -butyl}-lH-imidazole, 59. 4,5-dichloro-1-{4- (2-pyrimidinyl)-1-piperazill- butyl} H- imidazole, 4-chloro-1-{4- (4-xethoxyphenyl) -1-piperazilyl] RAE, _I'I but lH-pyrazole, 57 61. 4, 5 dichloro- 2 -methy1- 1 -methoxyphelyl) 1-piperazinyl] butyl} -1H-imidazole, 62.' 4-chloro-1-{4- (2-methoxyphenyl) -1-piperazinyl] butyl} -1H-pyrazole, 63. 4,5-dichloro-2-methyl-1-{4- (2-metho~xyphelyl) 1-piperazinyl] butyl}-1H-imidazole, 64. 4-chloro-1-{4- (3-methoxyphenyl) -1-piperazinyl] butyl) -1H-pyrazole, (4-methoxyphenyl) -1-piperazinyllbutyl}pyr- role, 66. [4 (2 -methoxyphenyl) 1-piperazinyll butyl~pyr- role, 67. (phenyl) -1-piperazinyllbutyl}pyrroJle, 68. 4-chloro-1-{4- (phenyl) -1-piperazinyllbutyl}-1H- pyrazole, 69. 4,5-dichloro-2-methy1-l-{4-[4-(phel)-1-piper- azinyl] butyl}-lH-imidazole, 4-chloro-1-{4- (2-chiorophenyl) -1- piperazinyl] butyl}-1H-pyrazole, 71. 4,5-dichloro-2-methy1-l-{4-[4-(2-chlorophelyl)- 1-piperazinyl] butyl} -1H-imidazole, 72. 4-chloro-1-{4-[4-(3-ch1orophefl)-1- piperazinyl] butyl)-lH--pyrazole,

253. 4,5-dichloro-2-znethyl-1-{4-(4-(2-cyalopheflyl)- 1-piperazinyllbutyl}-1H-imidazole, 74. 4, 5-dichloro-2-met-hy1-1-{4-[(4- (2-f1luorophelyl) 1-piperazinyl] butyl) -lH-imidazole, 4-chloro-1-{4- (2-cyanophenyl) -1- piperazinyl] butyl}-1Ii-pyrazole, 76. 4,5-dichloro-2-znethy1-1-{4-[4-(3-trif1uoromethyl- phenyl) -1-piperazinyl] butyl}-1H-imidazole, 77. 4 -chloro- 1- [4 (3 -trif luoromethylphelyl) 1-piperazinyl] butyl} -1H-pyrazole, 78. 4-chloro-1-{4- (2-fluorophenyl) -1- -piperazinyllbutyl}-lH-pyrazole, 79. 4-hoo1{-(-(,-eziohao--l 1ppr azinyl] butyl} -1H-pyrazole, 4,5-dichloro-2-methy1-1-{4-(4-(1,2-belzisothiazol- 3-yl) -1-piperazinyllbutyl}-1H-imidazole, 58 81. 1 ,2-benzisothiazol-3-yl)-1 -piperazinyl]butyl}-1 H-i ,2 ,4-triazole, 82. 1 1,2-benzisothiazol-3-y)-1 -piperazinyl]butyl}-1 H-benzimidazole, 83. 4-bromo-lI-{4-[4-(5-bromopyrimid in-2-yl)-1 -piperazinyl]butyl}-1 H-pyrazole, 84. 4-chloro-{4-[4-(5-bromopyrimidin-2-yI)-1 -piperaziny]butyl}-1 H-pyrazole. 11. A method according to any one of claims 4-9 wherein said compound is 4-chloro-1 -{4-[4-(2-pyrimidinyl)-1 -piperazinyl]butyl}-1 H-pyrazole d ihydrochioride. 12. A method according to claim 4 substantially as hereinbefore described with reference to any of the examples. DATED 7 October, 1998 PHILLIPS ORMONDE FITZPATRICK Attorneys For: LABORATORIOS DEL DR. ESTEVE, S.A. Does& C:\WINWORO .JENNYMNSPECNKI\13764-97.DOC